Substance P (hereinafter, referred to as “SP”) is a peptide consisting of 11 amino acids, and the amino acid sequence thereof is Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (SEQ ID NO: 10), wherein a carboxyl group of a C-terminal amino acid is amidated, and the same applies below.
SP belongs to the tachykinin peptide family. Here, the term “tachykinin peptide family” (or “tachykinin family”) refers to a peptide family having FXGLM-NH2 (SEQ ID NO: 22) where X denotes a hydrophobic amino acid) at the C-terminus. SP is found not only in vertebrates, but also in invertebrates. It is involved in inflammation, pain, itch, muscular contraction, and the like, and it has various functions in an organism. Therefore, the discovery of a novel antagonist against SP is thought to contribute to the development of remedies for suppressing various symptoms in which SP is involved (e.g., pain, inflammation, and itch).
Antagonists against SP have been developed on the basis of non-peptide-derived antagonists and peptide-derived antagonists. Non-peptide-derived antagonists can be synthesized in large amounts, but the antagonists that have been developed to date are problematic in that they dissolve only in organic solvents and can cause adverse reactions when they are administered to an organism. On the other hand, peptide-derived antagonists are advantageous in that they are water soluble. Hence, adverse reactions in an organism caused by peptide-derived antagonists less severe than adverse reactions caused by non-peptide derived antagonists. Therefore, peptide-derived antagonists have a higher utility value than non-peptide-derived antagonists in view of administration to an organism.
Meanwhile, endokinins (hereinafter, referred to as “EK”) are novel peptides discovered in 2003. Four types of endokinin are known: endokinin A (hereinafter, referred to as “EKA”), endokinin B (hereinafter, referred to as “EKB”), endokinin C (hereinafter, referred to as “EKC”), and endokinin D (hereinafter, referred to as “EKD”) (Non-patent document 1). Among EKs, EKC and EKD are referred to as tachykinin-related peptides, since they both have FXGLL-NH2 (SEQ ID NO: 23; where X denotes hydrophobic amino acid) instead of FXGLM-NH2 (SEQ ID NO: 22) that is a C-terminal consensus sequence of tachykinin peptides. In FXGLL-NH2 (SEQ ID NO: 23), “M” in FXGLM-NH2(SEQ ID NO: 22) is substituted with “L” (Non-patent document 2).
EKC and EKD are peptides each consisting of 14 amino acids. Both EKC and EKD have a consensus amino acid sequence except for the N-terminal 2 amino acids. The present inventors have discovered that intrathecal administration of a peptide (hereinafter, referred to as “EKC/D” and consisting of the amino acid sequence represented by SEQ ID NO: 1) consisting of the consensus amino acid sequence of these peptides to a rat does not induce scratching behavior or thermal hyperalgesia, which is pain-related behavior, whereas pre-administration of the peptide suppresses scratching behavior and thermal hyperalgesia induced by administration of SP or EKA/B (Non-patent document 3). The results indicate that EKC/D acts as an antagonist against SP.
The present inventors have also discovered that scratching behavior and thermal hyperalgesia induced by SP administration are suppressed by intrathecal administration of synthetic peptides in which M in the C-terminus of SP and EKA/B is substituted with L to a rat, as in Patent document 1. Specifically, they have discovered that these synthetic peptides act as antagonists against SP.
Also, Substance P-derived antagonists wherein some amino acids of SP are substituted with D-type amino acids,
antagonist D:(SEQ ID NO: 11)DArg-Pro-Lys-Pro-DPhe-Gln-DTrp-Phe-DTrp-Leu-Leu-NH2and Spantide I:(SEQ ID NO: 12)DArg-Pro-Lys-Pro-Gln-Gln-DTrp-Phe-DTrp-Leu-Leu-NH2(wherein DArg, DTrp, and DPhe denote D-arginine, D-tryptophan, and D-phenylalanine, respectively. Hereinafter, D-type amino acids are similarly denoted)have been reported (Non-patent document 4 (Antagonist D) and Non-patent document 5 (Spantide I)).